Herceptin Used First-Line for Breast Cancer Mets

Herceptin Used First-Line for Breast Cancer Mets

SAN ANTONIOIn a trial of first-line, single-agent therapy for
metastatic breast cancers that overexpress the HER-2 breast cancer
gene, Herceptin (trastuzu-mab) resulted in major objective responses
in 20% to 25% of patients. The monoclonal antibody is approved for
use as first-line therapy in combination with paclitaxel (Taxol) and
as a single agent in second- and third-line therapy.

The therapeutic antibody resulted in noteworthy response rates
in patients who had a history of adjuvant anthracycline therapy or
bone marrow transplantation, said Charles Vogel, MD, an
oncologist at Aventura Hospital, Aven-tura, Florida. Response rates
were similar with a 2 or 4 mg/kg/wk dose. Because toxicity was
greater with 4 mg/kg, the lower dose should be used, he said at the
San Antonio Breast Cancer Symposium.

Herceptin is active as a single agent in patients who have had
no previous therapy for metastatic breast cancer, Dr. Vogel
said. The therapy is well tolerated and has a favorable safety
profile. Severe adverse events are infrequent. The adverse events
common with cytotoxic chemotherapy are rarely seen.

The trial involved 112 women with metastatic breast cancers that
overex-pressed HER-2 by immunohistochemistry staining (either 2-plus
or 3-plus overexpression). The trial protocol excluded patients who
had received prior therapy for metastatic disease, but prior adjuvant
therapy was allowed. Two-thirds of the patients had received prior
adjuvant chemotherapy, and 55% had prior anthracycline therapy. Dr.
Vogel said that 12% had received bone marrow transplants. About half
had a history of radiation therapy, and 37% had prior hormonal treatment.

The patients had a mean age of 54. More than half were estrogen
receptor-negative. Three-fourths overexpressed HER-2 at the 3-plus level.

Patients were randomized to one of two doses of Herceptin: a 4 mg/kg
loading dose, followed by 2 mg/kg weekly, or an 8 mg/kg loading dose
and 4 mg/kg weekly. Efficacy assessment occurred at 8, 12, and 24
weeks, and then every 12 weeks thereafter.

At a median follow-up of 11 months, 37 patients have died, 20 in the
high-dose Herceptin arm and 17 in the low-dose arm. None of the
deaths occurred on study, Dr. Vogel said. All the deaths
occurred secondary to metastatic breast cancer. We had no
discontinuations for adverse events.

Response Rate

Six patients achieved a complete response, and 20 had a partial
response, resulting in an overall response rate of 23%. An additional
8% had disease stabilization for more than 6 months. The overall
response rate was 24% in the low-dose group and 22% in the high-dose group.

The treatment resulted in durable responses, with several persisting
beyond 2 years. The median time to progression has been 8.4 months in
responders and 10.8 months in patients who had prolonged disease
stabilization. These patients had clinically significant
stabiliza-tions that persisted beyond the median for responders,
Dr. Vogel commented.

Herceptin led to responses in 25% of patients who had liver
metastases, 31% of patients who overexpressed HER-2 at the 3-plus
level, 25% of patients who had a history of doxorubicin treatment,
and 38% of patients who had received bone marrow transplants. Because
of the brief follow-up period, survival cannot yet be assessed, he said.

Mild Toxicity

Toxicity was generally mild and infrequent. Leukopenia occurred in 1%
of patients, thrombocytopenia in none, anemia in 3% (2% severe),
stomatitis in 1%, and alopecia in 4% (1% severe). The most common
adverse events (occurring in 20% or more of patients) were asthenia,
nausea/vomiting, fever, chills, rash, headache, and diarrhea.

These adverse events were almost certainly due to Herceptin,
but they were generally mild and easily managed, Dr. Vogel said.

Although the overall incidence of adverse events was low, the
incidence was higher in the 4 mg/kg patient group. Given the
fact that there is more toxicity with the 4 mg/kg dose, the
recommended dose of 2 mg/kg should be adhered to, he said.

There have been three cases of cardiac dysfunction, defined as any
recognized symptoms of cardiac dysfunction or an asymptomatic
absolute decrease in ejection fraction of greater than 10%. An
independent review committee ruled that one case was secondary to
pericardial tamponade in a patient who had a history of pericardial
malignant effusion. The two other cases remain under review. Both
involved elderly patients with a history of heart disease, Dr. Vogel said.